WO2012077055A1 - Procédé de préparation d'un gel réticulé - Google Patents

Procédé de préparation d'un gel réticulé Download PDF

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Publication number
WO2012077055A1
WO2012077055A1 PCT/IB2011/055496 IB2011055496W WO2012077055A1 WO 2012077055 A1 WO2012077055 A1 WO 2012077055A1 IB 2011055496 W IB2011055496 W IB 2011055496W WO 2012077055 A1 WO2012077055 A1 WO 2012077055A1
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WIPO (PCT)
Prior art keywords
polysaccharide
process according
gel
aqueous gel
microns
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Application number
PCT/IB2011/055496
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English (en)
Inventor
Luc Sentier
François BOURDON
Original Assignee
Teoxane
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Publication of WO2012077055A1 publication Critical patent/WO2012077055A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
    • C08B37/006—Heteroglycans, i.e. polysaccharides having more than one sugar residue in the main chain in either alternating or less regular sequence; Gellans; Succinoglycans; Arabinogalactans; Tragacanth or gum tragacanth or traganth from Astragalus; Gum Karaya from Sterculia urens; Gum Ghatti from Anogeissus latifolia; Derivatives thereof
    • C08B37/0063—Glycosaminoglycans or mucopolysaccharides, e.g. keratan sulfate; Derivatives thereof, e.g. fucoidan
    • C08B37/0072—Hyaluronic acid, i.e. HA or hyaluronan; Derivatives thereof, e.g. crosslinked hyaluronic acid (hylan) or hyaluronates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
    • A61K8/04—Dispersions; Emulsions
    • A61K8/042—Gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
    • A61K8/73—Polysaccharides
    • A61K8/735—Mucopolysaccharides, e.g. hyaluronic acid; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/08—Anti-ageing preparations
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J3/00—Processes of treating or compounding macromolecular substances
    • C08J3/02—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques
    • C08J3/03—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques in aqueous media
    • C08J3/075—Macromolecular gels
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J2305/00—Characterised by the use of polysaccharides or of their derivatives not provided for in groups C08J2301/00 or C08J2303/00
    • C08J2305/08—Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof

Definitions

  • the present invention aims to propose a process for preparing hydrogels based on a crosslinked polysaccharide, and preferably on hyaluronic acid or a salt thereof.
  • Hyaluronic acid which is naturally present in the skin, is known for its viscoeiastie properties and also its high propensity to absorb water. Its properties explain to a large extent the elasticity of the skin, its biocompaiibilities, tolerance and lack of toxicity are such thai, for more than 10 years, this molecule has been used in medical and cosmetic fields, and in particular for filling wrinkles.
  • the injection into the dermis of a crosslinked hydrogel of polysaccharide at the wrinkles to he heated makes it possible to reduce, or even eliminate ' the local weakening of the structure of the dermis represented by a wrinkle.
  • the polysaccharide and more particularly the hyaluronic acid, is used in a crosslinked form given the increased resistance of this particular form to degradation and to heat.
  • crosslinked polysaccharide gels can be prepared by various preparation processes. Generally, these processes require two main steps, the first consisting in rehydrating the polysaccharide under consideration so as to convert it into an aqueous gel and die second aimed at bringing said aqueous gel into contact with, an agent capable of inducing the erosslfnking thereof. Depending on the specific conditions selected for the crosslinking, it proves to be possible to adjust the viscosity or else the theological properties of the crosslinked hydrogel formed.
  • the present invention aims precisely to propose a process for obtaining crosslinked gels having particularly advantageous mechanical properties
  • the present invention relates to a process for preparing a crosslinked gel of at least one polysaccharide or a salt thereof, comprising at least the steps consisting in:
  • step b) subjecting the mixture formed in step b) to conditions suitable for the sross!inkmg of said polysaccharide, and, if need be,
  • step c comprises, prior to step c), at least one step e) consisting in circulating the aqueous gel of polysaccharide of step a) and/or the mixture of step b) through at least oris extrusion device which has at least one filter with a porosity ranging from 2 to 100 microns and capable of retaining any particle with a diameter greater than 100 microns.
  • This step e) consisting in circulating the aqueous gel of polysaccharide and/or the mixture obtained at the end of step b) through an extrusion device as mentioned above, can also be demoted, in the rest of the present description, as an "extrusion step".
  • the device which has at least one filter that is used for carrying out extrusion step e) may also be denoted by the expression "extrusion device”.
  • the present invention results from the unexpected observation, by the inventors, that the implementation of an extrusion step makes it possible to obtain crosslinked polysaccharide gels having significantly improved viscoelastic properties, compared with the conventional crosslinking processes.
  • the improvement in the viscoelastic properties of the crosslinked gels obtained by implementing a process according to the invention can he explained by the fact that the extrusion step mostly contributes to a better organization of the polysaccharide chains or even, in addition, as appropriate, to protecting the aqueous gel of step a) and/or the mixture of step b) against a significant amount of residual particles or agglomerates which, for obvious ⁇ reasons, are prejudicial to good homogeneity thereof and therefore to the homogeneity of the crosslinked gels relating thereto.
  • the process can also comprise a step f) of stopping the crosslinldng, consisting in exposing the crosslinked gel to conditions suitable for stopping its crosslinking, it being possible for this step to be carried out prior to, jointly with or after the recovery step d).
  • step f) is carried out prior to step d).
  • the crosslinked gel obtained at the end of the process described above is a single-phase gel and more particularly a predominantly elastic viscoekstic gel, i.e. a gel with a reduced ability, or even devoid of the ability, to flow in the absence of stresses other than its own weight, like, for example, a gum.
  • the present invention relates to the use of a crosslinked gel obtained by implementing a process as defined above, for the long-lasting filling of volume defects of the skin, and in particular the filling of wrinkles.
  • a process according to the invention requires, firstly, providing at least one aqueous gel of at. least one polysaccharide in a noncrosslinked form in accordance with the invention.
  • step a This relates more particularly to step a).
  • noncrosslinked is intended to denote an aqueous gel of polysaccharide which is noncrosslinked or weakly crosslinked, i.e. a gel of which the phase shift angle ⁇ , measured by dynamic theology of 1 Hz, is greater than 40° when it is subjected to a stress greater than 1 Pa.
  • Such an aqueous gel can be obtained by bringing together at least one aqueous medium and polysaccharide, in an appropriate receptacle, and homogenizing jointly with and/or subsequent to the addition of said polysaccharide to said aqueous medium, or vice versa.
  • the homogenization step considered above should be carried out in such a way as to form homogeneous structures.
  • a process according to the invention requires the addition, to said aqueous gel of polysaccharide obtained in step a), of an effective amount of crosslinking agent. This relates more particularly to step 3 ⁇ 4).
  • the term "effective amount” is intended to mean, an amount of crosslinking agent which, in relation to the amount of polysaccharide under consideration,, allows satisfactory crosslinking of the aqueous gel of polysaccharide.
  • step b) is carried out over a period of greater than 5 miimtes, preferably ranging from 15 to 180 minutes.
  • this step b) can also be accompanied by at least one further step of honiogenization jointly with and3 ⁇ 4r subsequent to the addition of said crosslinking agent.
  • step b) of bringing an aqueous gel of polysaccharide in noncross!inked. form into contact with a crosslinking agent is carried oat under conditions not suitable for effective implemen tation of the crosslinking.
  • steps a) and/or b) involve(s) at least one homogernzation.
  • the objective of this operation is more particularly to completely hydrate and homogenize the polysaccharide in the aqueous medium and, where appropriate, the crosslinking agent, and thus to contribute to the optimization of the qualities of the expected crosslinked gel.
  • the homogeneity of the crosslinked gel is closely linked to the homogeneous nature of the gel before crosslinking.
  • the homogenization is considered to be satisfactory when the solution obtained has a homogeneous coloration, without agglomerates, and a uniform viscosity. It can advantageously be carried out under mild operating conditions in order to prevent degradation of the polysacch aride chains.
  • This step is all the more important when the polysaccharide has a high molecular weight.
  • the hydration of such a compound then in fact has a tendency to generate the formation of a solution of high viscosity within which the appearance of agglomerates is commonly observed.
  • the duration of this honiogenization step therefore depends on the nature of the polysaccharide, and more particularly on its molecular weight, on its concentration, on the operating conditions within the aqueous medium and also on the homogenization device used,
  • the adjustment of the duration of homogenization suitable for obtaining a sufficiently homogeneous aqueous gel of polysaccharide is part of the general knowledge of those skilled in the art.
  • a homogenization step according to t!ie present invention can be carried out over a period of less than 200 minutes, preferably less than 150 minutes, or even between 15 and 100 minutes.
  • the aqueous gel of step a) and/or the mixture of step b) is (are) subjected to at least one extrusion step e).
  • This extrusion step e) consists in circulating the aqueous gel of polysaccharide of step a) and/or the mixture obtained at the end of step b) through at least one extrusion device which has at least one filter with a. porosity ranging from 2 to 100 microns and capable of retaining any particle with a diameter of greater than 100 microns.
  • the objective of this step is to organize the polysaccharide chains and, if need be, to protect the gel from possible residual particles prejudicial to its homogeneity, before crossliriring step c).
  • this step is also advantageous in that it allows an improvement in the homogenization of the aqueous gel of step a) and/or of the mixture of step b).
  • extrusion step e) takes place prior to step c).
  • it can take place prior to, jointly with and/or after step b) of bringing the aqueous gel of polysaccharide into contact with the crosslinking agent.
  • extrusion step e) is carried oat after step b) of bringing the aqueous gel of polysaccharide of step a) into contact with the crosslinking agent or, in other words, on the mixture of step b).
  • step e) in particular when it takes place after step b), is carried out under conditions suitable for keeping the gel in the nonerosslinked state* as defined above.
  • step e) is carried out at a temperature of less than 25°C, preferably at a temperature ranging from 15 to 25°C, and better still at ambient temperature.
  • the implementation of extrusion step e) is part of the general knowledge of those skilled in the art.
  • the characteristics of the filter are determined from the viewpoint of the molecular weight(s) of polysaccharide(s) used.
  • the filter consists of at least one screen or fabric, which is preferably metallic, composite or polymeric in nature.
  • extrusion step e) is carried out by means of at least one extrusion device comprising at least one filter with a porosity ranging from 5 to 50 microns, better still from 8 to 30 microns, and more particularly with a porosity of 10 microns.
  • the rate at which the aqueous gel of step a) and/or the mixture obtained at the end of step b) passes through said device is also a parameter that is part of the general knowledge of those skilled in the art.
  • the linear rate of extrusion of the aqueous gel of step a) and/or of the mixture obtained at the end of step b) through the extrusion device ⁇ s) is slow so as not to degrade the polysaccharide chains during their passage therethrough.
  • the linear rate of extrusion of said aqueous gel of step a) and/or mixture obtained at the end of step b) through the extrusion device(s) is between ! and 100 cm per minute, preferably between 1 and 4 cm per minute.
  • This rate depends on the porosity and the nature of the filter, on the polysaccharide under consideration and also on the amount of material to be treated.
  • An aqueous gel of step a) and/or of mixture of step b) can be placed in a system comprising a tank fitted with a piston and. at the outlet of said system s with at least one extrusion device as described above.
  • extrusion step e) can result from the use of extrusion devices in a cascade, having filters with different, and preferably decreasing, porosities,
  • This particular embodiment is particularly advantageous in so far as it makes it possible to achieve crosslinked hydrogels having further improved viscoelastie properties. This is because this cascade system allows the polysaccharide chains to be organized and also allows an extrusion that is gradual and, consequently, less aggressive with respect to the degradation of said polysaccharide chains,
  • extrusion step e) is to be distinguished from a conventional filtration which results, for purification purposes, in the separation of components initially included in the composition to be purified.
  • step b the mixture obtained at the end of step b), whether or not it is subjected to an intermediate extrusion step e), is then subjected to conditions suitable for crosslinking.
  • the objective of the crosslinking is to create bridges between the polysaccharide chains, and in particular hyaluronic acid chains, allowing a solid and dense three dimensional network to be obtained from a viscous solution.
  • the crosslinking step requires particular conditions which depend simultaneously on the nature of the polysaccharide, on its molecular weight on the aqueous medium and on the nature of the crosslinking agent.
  • condition is intended to denote the component which initiates the crosslinking, such as, for example, heating or IJV exposure,
  • an initiating component can be implemented by:
  • IJV type radiation of certain wavelengths of IJV type, for example to microwave radiation or to infrared;
  • the crosslinking step is carried out thermally.
  • the heating means and the intensity of said healing means are of course adjusted from the point of view of the mode of crossiinking, the degree of crossiinking and the viscosity of the gel that are desired,
  • a temperature particularly suitable for crosslinkiffig step e) depends on the nature of the polysaccharide under consideration.
  • a temperature particularly suitable for crossiinking step e) is between 25 and 60°C, preferably between 45 and 55°C, and better still between 48 and 52°C. .
  • the degree of cross!inking also depends on the duration of ctosslirsking to which the mixture obtained at the end of step b) is subjected, whether or not, prior to crossiinking step e), it is subjected to an extrusion step e).
  • crossiinking step c) can be carried out over a period ranging from 30 to 300 minutes, preferentially from 100 to 200 minutes, and better still from 150 to 190 minutes.
  • the crossiinking conditions are adjusted so as to obtain a maximum crossiinking efficiency, i.e. the obtaining of a maximum level of actual crossiinking for a minimum amount of crossiinking agent used.
  • the crossiinking conditions are adj usted is order to obtain a degree of crossiinking such that the product formed is viseoelastie, or even solid.
  • crosslinkirsg step c) is carried out in a basic medium, the receptacle containing the corresponding gel, in particular of hyaluronic acid, being placed in a thermostatic bath brouglit to a temperature of about from 50 to 55°C, for a period at least equal to 1 h 30, and preferably between 2 h 30 and 3 h 10.
  • the crossiinking can be stopped ' (step f)) prior to, jointly with or after step d) of recovering the gel
  • Such a step requires exposing the crosslinked gel or gel undergoing crossiinking. or even the receptacle containing it, to conditions suitable for stopping said crossiinking, or else to conditions capable of stopping the formation of bonds between the various polysaccharide chains.
  • step f) is carried out prior to step d).
  • the erosslinking can be stopped:
  • said erosslinking is stopped by stopping fee exposure of said gel to the radiation.
  • a process of the invention can be carried out at least partly within a specific receptacle having a deforniabie wall, such as, for example, a pouch.
  • the specific receptacle can be fitted with a closable opening system or gate, suitable for introducing any compound of use in the production of a gel in accordance wife the invention.
  • the extrusion step described above requires the aqueous gel of step a) and/or fee mixture obtained at the end of step h) to pass through at least one extrusion device.
  • This step consequently implies that said gel and/or mixture is (are) no longer included in the specific receptacle described above.
  • Such a system can, for example, he characterized by use of at least two specific receptacles, the first receptaele s devoted in particular to fee preparing of the aqueous gel of polysaccharide of step a) and, where appropriate, of the mixture obtained at the end of step b), and also the hornogenization thereof, being connected to fee extrusion device, itself connected to the second receptacle, devoted to the recovery of the aqueous gel of step a) and/or mixture of step b) after the extrusion step, and to the implementation of the step c) for crosslinking and, where appropriate, for stopping the crosslinking.
  • the crosslinked gel obtained at the end of the process as described above cannot generally be injected directly, in particular because of its polysaccharide concentration is too high and because of tlie possible presence of crosslinking agent residues or else because of its physiological or pH conditions.
  • the gel obtained at the end of the implementation of tlie process as described above can in particular have too great a stiffness to be injected as such into a patient.
  • a step of protecting and redensifying tlie gel can also be carried out in order to further improve the qualities of the implant, according to the know-how of those skilled in tlie art.
  • the gel must be physiologically formulated by virtue of the presence of salts in amounts equivalent to those of the medium injected.
  • an additional purification step may also be carried out.
  • the final step consists in filling syringes with the gel, which is carried out under controlled atmospheric conditions, followed by a final thermal sterilization which takes place immediately after the filling of the syringes.
  • polysaccharide in accordance with the invention is intended to mean any polymer consisting of several monosaccharides linked together by O-glycoside bonds and having the general formula: ⁇ [C x (H 2 O ⁇ y)] n -.
  • a polysaccharide in accordance with the invention is more particularly selected with regard to the properties that it is desired to see the crosslinked gel obtained according to the invention display, More particularly, such a polysaccharide must have good biocompatibiliry.
  • a physiologically acceptable polysaccharide or polysaccharide salt may be of natural or synthetic origin.
  • the polysaccharide suitable for the invention may in particular be chosen from chondroi tin sulphate, keratam keratan sulphate, heparin, heparin sulphate, xanthan, carrageenaii, hyaluronic acid, chitosan, cellulose and derivatives thereof, alginate, starch, dextran, pulMan, galactomannan and biologically acceptable salts thereof.
  • polysaccharide salts in accordance with the invention are more particularly chosen from physiologically acceptable salts, such as the sodium salt, the potassium salt, the zinc salt and the silver salt, and mixtures thereof, preferably the sodium salt,
  • a polysaccharide or polysaccharide salt according to the invention has a high molecular weight, preferably a molecular weight greater than or equal to 100 000 Da, better still greater than or equal to IMDa (or 1 x 10 6 Da), or even greater than 3 MDa (or 3 x 10 6 Da), depending on the application under consideration.
  • One particularly preferred polysaccharide is hyaluronic acid or a salt thereof, preferably sodium hyaluronate (NaHA),
  • Step a) of a process of the invention consists in providing an aqueous gel of polysaccharide, or of a salt thereof, in a noncrosslinked form.
  • the polysaccharide is present within the aqueous gel of said polysaccharide in a noncrosslinked form in a content of between 5 and 15% by weight, preferably in a content greater than 10% by weight, relative to the total- weight of said aqueous gel.
  • Such an aqueous gel is obtained by formulation of said polysaccharide in an aqueous medium.
  • aqueous medium is intended to mean any liquid medium containing water and which has the property of dissolving a polysaccharide or a salt thereof.
  • aqueous medium is more particularly dependent on the type of crosslinking envisaged, but also on the type of polymer used.
  • an aqueous medium that may he suitable may be either acidic or hasic.
  • a particularly preferred aqueous medium is an alkaline medium, preferably sodium hydroxide (NaGH), more particularly a solution of sodium hydroxide having a pH greater than 12.
  • Crosslinking agent in accordance with the invention is intended to mean any compound capable of inducing crosslinking between the various polysaccharide chains.
  • a crosslinking agent in accordance with the invention is chosen from epoxide, aldehyde, polyaziridyl. divinylsulphone (DVS) and mixtures thereof
  • a crosslinking agent in accordance with the invention is chosen from epoxy crosslinking agents which are preferably Afunctional or multifunctional, and more particularly chosen from 1 ,4-butanediol diglycidyl ether (BDDE), diqxixyoetane or 1,2- hi s(2 , 3 -epoxypropyl) ⁇ 2,3 -ethyl ene.
  • BDDE 1 ,4-butanediol diglycidyl ether
  • diqxixyoetane diqxixyoetane or 1,2- hi s(2 , 3 -epoxypropyl) ⁇ 2,3 -ethyl ene.
  • the crosslinking agent is 1 ,4-butanediol diglycidyl ether.
  • the adjustment of the amount of crosslinking agent for carrying out the crosslinking reaction is also clearly within the competence of those skilled in the art.
  • the expression '"effective amount is intended to denote an amount sufficient to obtain the expected effect.
  • the process according to the invention uses sodium hyaluronate in an alkaline medium with 1 ,4-butanediol diglycidyl ether as crosslinking agent.
  • FIGURE
  • FIG. 1 illustrates the viscoelastk properties of hyaluronic acid gels measured by their elastic modulus (G' in Pa).
  • G' in Pa elastic modulus
  • the preparation protocol is as follows:
  • the protocol is the same as that described for product A ; but carried out with, ailer step 2 of adding the BDDE and 15 min of bomogenization, an extrusion step, at ambient temperature, consisting in circulating the mixture obtained at the end of step 2 through an extrusion device comprising a filter, respectively, of 10 microns (product B) and 50 microns iproduct B').
  • This extrusion step is carried out over a maximum period of 5 minutes.
  • the mixture obtained at the end of step 2 is thus placed in a tank, the outlet of which is a cylindrical section fitted with, a screen filter with a porosity of, respectively, 10 and 50 ⁇ , and a diameter of 55 mm, in particular a screen filter such as those sold by the company Rubber Fab, under the name "Platinum Screen Gasket”.
  • the pressure applied to the mixture is adjusted such that the linear rate of extrusion is about 4 cni ⁇ min, which represents a flow rate of about 100 cm7min.
  • All of the products A, B and B' are packaged In syringes.
  • the viscoelastic properties of these products are measured using a rheometer (Haake RS6000) with a cone/plate geometry (TV 35 mm diameter).
  • a stress sweep is carried out, and the elastic modulus.
  • G' (in Pa) and the phase shift angle ⁇ (°) are measured at I Hz for a stress of 5 Pa.
  • Figure 1 hereinalter represents the values of the elastic moduli G' (in Pa).
  • the value of the phase shift angle ⁇ (°) is indicated at the top of each column, to the right of the G' value.
  • phase shift angle measured is extremely small, which means that these gels exhibit a mainly elastic (solid) nature.

Abstract

La présente invention concerne un procédé de préparation d'un gel réticulé d'au moins un polysaccharide ou un de ses sels, comprenant au moins les étapes suivantes : a) utilisation d'au moins un gel aqueux dudit polysaccharide sous une forme non réticulée ; b) mise en contact dudit gel aqueux avec une quantité efficace d'au moins un agent de réticulation ; c) soumission du mélange formé lors de l'étape b) à des conditions appropriées pour la réticulation dudit polysaccharide ; et, en cas de besoin d) récupération dudit gel réticulé. Ledit procédé comprend, avant l'étape c), au moins une étape e) consistant à faire circuler le gel aqueux du polysaccharide de l'étape a) et/ou du mélange de l'étape b) à travers au moins un dispositif d'extrusion, qui possède au moins un filtre présentant une porosité de 2 à 100 microns et est apte à retenir toute particule présentant un diamètre supérieur à 100 microns.
PCT/IB2011/055496 2010-12-06 2011-12-06 Procédé de préparation d'un gel réticulé WO2012077055A1 (fr)

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FR1060136A FR2968306B1 (fr) 2010-12-06 2010-12-06 Procede de preparation d'un gel reticule
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US8883139B2 (en) 2010-08-19 2014-11-11 Allergan Inc. Compositions and soft tissue replacement methods
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US9228027B2 (en) 2008-09-02 2016-01-05 Allergan Holdings France S.A.S. Threads of Hyaluronic acid and/or derivatives thereof, methods of making thereof and uses thereof
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US10905797B2 (en) 2010-03-22 2021-02-02 Allergan, Inc. Polysaccharide and protein-polysaccharide cross-linked hydrogels for soft tissue augmentation
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US11083684B2 (en) 2011-06-03 2021-08-10 Allergan Industrie, Sas Dermal filler compositions
US11844878B2 (en) 2011-09-06 2023-12-19 Allergan, Inc. Crosslinked hyaluronic acid-collagen gels for improving tissue graft viability and soft tissue augmentation

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